The invention pertains to novel N-(phenylalkyl)amide and urea derivatives having drug and bio-affecting properties and to their preparation, pharmaceutical formulations and use. In particular, the invention concerns N-(phenylalkyl)amides and ureas having a meta-alkoxy substituent in the phenyl ring. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. Melatonin levels show a cyclical, circadian pattern with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms and the modulation of retinal physiology.
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [.sup.125 I]-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the CNS of a variety of species. The sequence of one such high affinity melatonin receptor, cloned from frog dermal melanophores, has been reported (Ebisawa, et al., Proc. Natl. Acad. Sci. 91:6133-6137, 1994). In mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures. Although there are significant differences in melatonin receptor distribution even between closely related species, in general the highest binding site density occurs in discreet nuclei of the hypothalamus. In humans, specific [.sup.125 I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting the melatonin receptors are located within the human biological clock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al., J. Biol. Rhythms, 1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al., Br. Med. J. 292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487. Thus, melatonin agonists should be particularly useful for the treatment of sleep disorders and other chronobiological disorders. Melatonin agonists would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, immune disorders, and neuroendocrine disorders.
Aside from simple indole derivatives of melatonin itself, various bicyclic structures have been prepared and their use as melatonin ligands disclosed. In general these bicyclic amide structures can be represented as: ##STR2## wherein Z is an aryl or heteroaryl system attached by a two carbon bridge to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application EPA 527 687A disclose as melatonin ligands arylethylamines 1, ##STR3## wherein Ar' is, inter alia, a substituted or unsubstituted benzo[b]thiophen-3-yl, benzimidazol-1-yl, benzo[b]furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R.sub.1 is, inter alia, an alkyl or cycloalkyl group; and R.sub.2 is hydrogen or lower alkyl.
Horn and Dubocovich, in European Patent Application EPA 420-064A, disclose 2-amidotetralins 2 as melatonin ligands, ##STR4## wherein R.sub.1 is, inter alia, hydrogen, lower alkyl, or lower alkoxyl; R.sub.2 is, inter alia, hydrogen, halogen, or lower alkoxyl; R.sub.3 is; inter alia, hydrogen, or lower alkyl; R.sub.4 is, inter alia, lower alkyl, haloalkyl or cycloalkyl; and R.sub.5 is hydrogen, hydroxyl, halogen, oxo, aryl, lower alkyl or alkylaryl.
Yous, et al. in European Patent Application 506 539A claim melatonin ligands 3, ##STR5## wherein A is oxygen or sulfur; X is a methylene group or a bond; and R is H or lower alkyl when p is 1 and B is defined by the radical 4, ##STR6## wherein R.sub.1 is hydrogen or lower alkyl and R.sub.2 is, inter alia, hydrogen, lower alkyl or cycloalkyl. Alternatively, R is defined by the radical 4 when p is 0 or 1 and B is lower alkoxy.
Several naphthalene derivatives have also been disclosed as melatonin ligands.
Andrieux, et al. in European Patent Application 447 285A claim amidoalkylnaphthalenes 5, ##STR7## wherein R is lower alkyl; R.sub.1 is hydrogen or lower alkyl; and R.sub.2 is, inter alia, hydrogen, lower alkyl, or cycloalkyl.
Yous, et al. in European Patent Application 562 956A disclose amide and urea naphthalene derivatives 6, ##STR8## in which R is hydrogen or OR.sub.4 wherein R.sub.4 is, inter alia, hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; R.sub.1 is hydrogen or COOR.sub.5 wherein R.sub.5 is hydrogen or alkyl; R.sub.2 is hydrogen or alkyl; X is NH or a bond; and R.sub.3 is, inter alia, alkyl, alkenyl, or cycloalkyl.
Lesieur, et al. in European Patent Application 530 087A disclose naphthylethylureas and naphthylethylthioureas 7, ##STR9## in which R is hydrogen or OR.sub.3 wherein R.sub.3 is, inter alia, hydrogen, lower alkyl, or cycloalkyl; R.sub.1 is hydrogen or lower alkyl; X is oxygen or sulfur; and R.sub.2 is, inter alia, lower alkyl or cycloalkyl.
Langlois, et al., in Australian Patent Application AU-A48729/93 disclose arylalkyl(thio)amides 8 as melatonergic ligands, ##STR10## wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is hydrogen, halogen, or lower alkyl; R.sub.3 and R.sub.4 are identical or different groups including, inter alia, hydrogen, halogen, or lower alkyl; R.sub.5 is hydrogen or lower alkyl; and R.sub.6 is, ##STR11## wherein X is sulfur or oxygen and R.sub.7 is, inter alia, lower alkyl or alkenyl. The disclosure specifies that the inventors have "discovered that new compounds of arylalkyl(thio)amide structures, substituted on their benzene ring with a hydroxyl or alkoxy radical specifically at the ortho position with respect to the alkyl(thio)amide chain, possessed very considerable activity with respect to the melatoninergic system, whereas these properties are not encountered with compounds substituted at the meta or para position with respect to the alkyl(thio)amide chain."
Copinga et al, in J.Med. Chem., 1993, 36, p. 2891, discusses amidomethoxytetralins of structure 9 and their melatonergic properties. ##STR12## In structure 9, R.sub.1 is H or OCH.sub.3 and R.sub.2 is alkyl, haloalkyl, phenylalkyl or phenyl.
In a comparative study, Copinga et al showed that compound 10 had markedly inferior [.sup.125 I]-2-iodomelatonin binding properties. ##STR13##
The foregoing disclosures do not teach or suggest the novel melatonergic phenylalkylamides or ureas of the present invention. The novel compounds of the present invention display enhanced melatonergic activity, in contradistinction to the prior art, with meta-substitution on the aryl ring and preferably a C3 or C4 bridge to the amide functionality.